tbuckley/cabot-search huggingface dataset:
Neoadjuvant immunotherapy in gastrointestinal cancers – The new standard of care?
Authors: Branka Petricevic, Julijan Kabiljo, Rebecca Zirnbauer, Henning Walczak, Johannes Laengle, Michael Bergmann
Journal: Seminars in Cancer Biology (2022)

The development of immune checkpoint inhibitors (ICI) offers novel treatment possibilities for solid cancers, with the crucial benefit of providing higher cure rates. These agents have become part of standard treatments in the metastatic and adjuvant setting for select cancers, such as melanoma, non-small cell lung cancer (NSCLC) or urological malignancies. Currently, there is ample clinical interest in employing ICI in a neoadjuvant setting with a curative intent. This approach is especially supported by the scientific rationale that ICI primarily stimulate the host immune system to eradicate tumor cells, rather than being inherently cytotoxic. Aside from tumor downstaging, neoadjuvant immunotherapy offers the potential of an in situ cancer vaccination, leading to a systemic adjuvant immunological effect after tumor resection. Moreover, preclinical data clearly demonstrate a synergistic effect of ICI with radiotherapy (RT), chemoradiotherapy (CRT) or chemotherapy (ChT). This review harmonizes preclinical concepts with real world data (RWD) in the field of neoadjuvant ICI in gastrointestinal (GI) cancers and discusses their limitations. We believe this is a crucial approach, since up to now, neoadjuvant strategies have been primarily developed by clinicians, whereas the advances in immunotherapy primarily originate from preclinical research. Currently there is limited published data on neoadjuvant ICI in GI cancers, even though neoadjuvant treatments including RT, CRT or ChT are frequently employed in locally advanced/oligometastatic GI cancers (i.e. rectal, pancreatic, esophagus, stomach, etc.). Utilizing established therapies in combination with ICI provides an abundance of opportunities for innovative treatment regimens to further improve survival rates.
An innovative strategy to continence recovery: The potential role of Human Dental Pulp Stem Cells to urethral sphincter regeneration
Authors: A. Zordani, M.S. Mangano, B.F. Beniamin, C.G. Carnevale, A.P. Pisciotta, C.L Lamon, G.B. Bianchi, S.M. Micali
Journal: European Urology (2022)
Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Christopher G Cann, Sarah Cimino, Brian Grieb, Kristen Keon Ciombor, Rajiv Agarwal, Satya Das, Laura Williams Goff, Dana Backlund Cardin, Shemeka Davis, Casey Fletcher, Jordan Berlin, Cathy Eng
Journal: Journal of Clinical Oncology (2022)

3559 Background: Colorectal cancer remains a significant source of morbidity and mortality within the United States, causing nearly 53,000 deaths in 2021. For unresectable pts, the estimated 5-year survival rate is 14%. Given recent advances in treatment, 50% of pts with mCRC will receive third-line therapy or greater, making optimization of therapy in these settings pivotal. Trifluridine-tipiracil (TAS-102) is FDA approved for third-line or greater in mCRC per the RECOURSE Trial. Standard dosing is 35 mg/m 2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles. This dosing schedule is associated with Grade 3-4 neutropenia (38%), requiring treatment delays (53%), dose reductions (14%) and G-CSF support (9%). To reduce this toxicity while maintaining efficacy, we studied an alternative biweekly dosing (Days 1-5 and Days 15-19 of 28-day cycles). Methods: A retrospective analysis was completed (2019-2021) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed &gt; 12 days of TAS-102 therapy. Diagnostic imaging was completed every 8-12 weeks. Patient data was evaluated for lines of prior therapy, ECOG performance status (PS), the addition of bevacizumab, and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was performed only in mCRC pts. Results: 24 pts met the criteria, with a mCRC:appendiceal CA ratio of 20:4 and Male:Female 13:11. Median age 61.5 yrs (range 31-80); median number of prior therapies 3; median ECOG PS of 1; and median duration of therapy 73.5 days. Hematologic toxicities: Neutropenia 30% [Grade 3 (13%), Grade 4 (0%)]; anemia 17.4% [Grade 3 (8.7%), Grade 4 (0%)]; thrombocytopenia 4.3% [Grade 3/4 (0%)]. No pts required G-CSF. One patient required a treatment-related dose delay (neutropenia), and 2 pts required dose reductions (fatigue). In mCRC pts, the median PFS was 2.3 months. To date, 7 mCRC pts remain on treatment (range: 38-385). Conclusions: In our retrospective cohort analysis, TAS-102 biweekly dosing schedule (35 mg/m 2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA reduced Grade 3 myelotoxicity without Grade 4 toxicities, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this is the first analysis of biweekly TAS-102 in a US patient population.
Clinical images: Granulomatosis with polyangiitis and transthyretin‐related amyloidosis
Authors: Justas Grimalauskas‐Suchina, Frank Behrendt, Corina Schuster‐Amft, Katrin Parmar, Leo Bonati, Hans U. Gerth
Journal: Arthritis & Rheumatology (2022)

The patient, a 62-year-old man, was admitted with acute inflammation, arthralgia, and fever. Laboratory tests indicated elevated C-reactive protein, leukocytosis with left shift, slight elevation of transaminase, and serum negativity for rheumatoid factor, anti–cyclic citrullinated peptide, and antineutrophil cytoplasmic antibodies. Computed tomography (CT) of the abdomen showed bilateral pyelonephritis. The patient was started on antibiotics, but after lack of response, this was changed to prednisolone, leading to rapid improvement and treatment phase out. Four weeks after first admission, the patient presented with new-onset sinusitis, cephalgia, and pharyngitis, clearly indicating another humoral inflammatory reaction. CT of the paranasal sinuses revealed polypoid chronic inflammatory mucosal swelling of both maxillary sinuses (A, arrow). Histologic analysis revealed necrotizing vasculitis, partly containing giant cells and granulocytes, which confirmed a diagnosis of granulomatosis with polyangiitis (GPA). The patient was started on systemic immunosuppressive therapy with prednisolone and methotrexate, which quickly led to remission. Further histologic analysis revealed pronounced amyloid deposits immunohistochemically positive for the transthyretin (TTR) subtype (B, arrows). A mutation in the gene encoding TTR (p.Arg54Gly) was confirmed. Subsequent 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy showed cardiac involvement by nuclide enhancement of the entire myocardium (C, arrow). The patient had pronounced muscle weakness and gait ataxia. Electroneurography confirmed mild sensorimotor mixed axonal–demyelinating polyneuropathy of the lower extremities. Congo red staining of the sural nerve indicated TTR deposits in the endoneurium (D, arrows). The patient was started on siRNA-based therapy with patisiran. This case is a rare coincidence of both TTR-related amyloidosis and GPA involving the upper respiratory tract, heart, and peripheral nerves. Open Access funding enabled and organized by Projekt DEAL. Disclosure Form: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
GCT-01. Pediatric intracranial germ cell tumors and primary polyuria-polydipsia syndrome: a 13-year single institutional experience
Authors: Rossana Pavone, Carla Fonte, Franco Ricci, Gaia Varriale, Giorgia Enrico, Maria Luigia Censullo, Carlotta Gemma Gori, Milena Guidi, Anna Maria Buccoliero, Chiara Caporalini, Lorenzo Genitori, Iacopo Sardi
Journal: Neuro-Oncology (2022)

Abstract Intracranial germ cell tumors (IGCTs) represent about 4% of all childhood brain tumors. They are common in both the pineal and pituitary regions and sometimes they can be bifocal. Suprasellar and bifocal IGCTs usually present stereotypical symptoms, including primary polyuria-polydipsia syndrome (PPS). Consolidated IGCTs’ therapy is based on the International Society of Pediatric Oncologic (SIOP) CNS GCT II protocol consisting of primary pre-radiation chemotherapy combining etoposide, carboplatin and/or cisplatin and ifosfamide. PPS management in these patients requires monitoring of electrolytes and fluids during chemotherapy, especially for cisplatin and/or ifosfamide-based cycles, for which hyperhydratation is required. We report the results of our single-center cohort of patients with IGCTs treated between 2008 and 2021, focusing on the clinical presentation, treatment and long-term follow-up. Thirty-one patients were analyzed (median age=13 years, 87% male). Twelve children (39%) presented a PPS and needed desmopressin treatment, maintained at long-term follow-up data update in all. Over these PPS patients, 6 had bifocal germinomas, 4 suprasellar germinomas, 1 metastatic germinoma and 1 non-germinomatous IGCT. Eleven PPS children (92%) received cisplatin and/or ifosfamide-based chemotherapy: all of them had optimal biochemical urine and blood investigations before, during and after chemotherapy. None of them presented serious complications during treatment. After a median follow-up of 5 years, two patients (6.5%) died (1 IGCT-related, 1 non-cancer related) and one had a second malignancy (parotid gland mucoepidermoid carcinoma, 6 years after IGCT diagnosis). Childhood IGCTs have an excellent prognosis, but present a significant risk of long-lasting severe endocrine sequelae which may be worsened by the primary oncological strategy, requiring careful management of complications related to fluid and electrolytes disturbances. In order to avoid post-treatment pituitary insufficiency, guidelines for diabetes insipidus management when cisplatin and/or ifosfamide-based protocols are used should be established and all patients should receive meticulous endocrine follow-up.
MODL-06. Targeting c-MET in combination with radiation is effective in MET-fusion driven high-grade glioma
Authors: Marc Zuckermann, Chen He, Jared Andrews, Roketa Sloan-Henry, Brandon Bianski, Jia Xie, Yingzhe Wang, Nathaniel Twarog, Arzu Onar-Thomas, Kati Ernst, Lei Yang, Yong Li, James Dalton, Xiaoyu Li, Divyabharathi Chepyala, Xiaoyan Zhu, Junyuan Zhang, Ke Xu, Laura Hover, Peter J McKinnon, Stefan M Pfister, Zoran Rankovic, Burgess B Freeman, Anang A Shelat, Jason Chiang, David T W Jones, Christopher L Tinkle, Suzanne J Baker
Journal: Neuro-Oncology (2022)

Abstract Oncogenic fusion events involving c-MET have been observed in up to 12% of pediatric high-grade glioma (pHGG). MET inhibitors have displayed potent initial responses in MET rearranged tumors but acquired resistance to single agent modalities invariably occurs. To identify new treatment options against these tumors, we established two novel orthotopic mouse models including an immunocompetent, murine allograft and an intracranial patient-derived xenograft (PDX), both harboring distinct MET fusions. We analyzed the pharmacokinetic and pharmacodynamic profiles of two MET inhibitors, crizotinib and capmatinib, and examined their efficacy against tumor cell cultures derived from the aforementioned models. Capmatinib outperformed crizotinib in terms of specificity, potency and brain availability, resulting in a highly differential cellular response compared to crizotinib treatment. We evaluated the efficacy of both compounds in combination with radiotherapy (RT) and found that radiation further potentiated the inhibitory effect of capmatinib on tumor cell growth. We then utilized both models to assess the combinatorial effect of capmatinib and radiation on intracranial tumors in vivo and found that the combination therapy significantly increased overall survival in both cohorts. In the PDX model, the combination, relative to either intervention alone, induced a remarkable decrease of tumor burden, which persisted throughout the observation period in all treated animals. RNA-sequencing of capmatinib-treated tumors and tumor cell cultures revealed impaired expression of DNA repair genes. Further, we showed that capmatinib enhanced radiation-induced DNA damage, as demonstrated by increased γ-H2AX foci in treated cells, providing mechanistic insight for the cooperative effects of the combined treatment. Our results validate capmatinib as an effective inhibitor of MET in pHGG and demonstrate the outstanding efficacy of capmatinib and radiation against MET-driven pHGG in two complementary preclinical models, informing future clinical trials.
Site-selective oral delivery of therapeutic antibodies to the inflamed colon via a folic acid-grafted organic/inorganic hybrid nanocomposite system
Authors: Sang Hoon Lee, Jae Geun Song, Hyo-Kyung Han
Journal: Acta Pharmaceutica Sinica B (2022)

This study aimed to develop a pH-responsive folic acid-grafted organic/inorganic hybrid nanocomposite system for site-selective oral delivery of therapeutic antibodies. A folic acid-grafted aminoclay (FA-AC) was prepared via an in situ sol‒gel method. Then, a drug-loaded nanocomplex was prepared via the electrostatic interaction of FA-AC with infliximab (IFX), a model antibody, and coated with Eudragit® S100 (EFA-AC-IFX). FA-AC exhibited favorable profiles as a drug carrier including low cytotoxicity, good target selectivity, and capability to form a nanocomplex with negatively charged macromolecules. A pH-responsive FA-AC-based nanocomplex containing IFX (EFA-AC-IFX) was also obtained in a narrow size distribution with high entrapment efficiency (>87%). The conformational stability of IFX entrapped in EFA-AC-IFX was well maintained in the presence of proteolytic enzymes. EFA-AC-IFX exhibited pH-dependent drug release, minimizing premature drug release in gastric conditions and the upper intestine. Accordingly, oral administration of EFA-AC-IFX to colitis-induced mice was effective in alleviating the progression of ulcerative colitis, while oral IFX solution had no efficacy. These results suggest that a pH-responsive FA-AC-based nanocomposite system can be a new platform for the site-selective oral delivery of therapeutic antibodies.
DIPG-44. H3K27-altered diffuse midline gliomas with secondary driver molecular alterations
Authors: Catherine Gestrich, Kristina Grieco, Hart Lidov, Keith Ligon, Sandro Santagata, Kee Kiat Yeo, Sanda Alexandrescu, David Meredith
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-altered, but their significance is not completely explored. We evaluated these associations in our institutional cohorts. MATERIALS AND METHODS: We searched our sequencing data base (2013-2020) for H3K27M-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Copy number profiles were evaluated using BioDiscovery's Nexus Copy Number software package. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. RESULTS: We identified 77 patients (age range 2-68, median 26). The diagnosis was DMG (n=55), anaplastic astrocytoma/glioblastoma (n=19), low-grade glioma (n=1), low-grade glioneuronal tumor (n=1), and ganglioglioma (n=1). Recurrent alterations were seen in TP53 (n=42), ATRX (n=17), NF1 (n=15), PDGFRA (n = 4). Five cases had BRAF V600E (1 ganglioglioma; 4 DMG); twelve had FGFR1 mutations (9 DMG; 3 anaplastic astrocytoma/glioblastoma). The most common location in the BRAF group was the brainstem and in the FGFR1 was the thalamus. Survival ranged from 0 to 97 months, median 12.9 months (28.8 months for FGFR1 and 22.8 for the BRAF V600E). This was not significantly different from OS reported in the literature for DMG.The BRAF V600E ganglioglioma patient is alive 37 months after diagnosis. CONCLUSION: There was no significant difference in outcomes for patients with secondary molecular drivers when compared with conventional H3K27M DMG. The outcome of the BRAF V600E tumors seemed to correlate with the histology. These findings and the possibility of targeted therapy argue for comprehensive sequencing of H3K27-altered gliomas.
Proteomics endotyping of infants with severe bronchiolitis and risk of childhood asthma
Authors: Tadao Ooka, Yoshihiko Raita, Michimasa Fujiogi, Robert J. Freishtat, Robert E. Gerszten, Jonathan M. Mansbach, Zhaozhong Zhu, Carlos A. Camargo, Kohei Hasegawa
Journal: Allergy (2022)

Bronchiolitis is the leading cause of hospitalization in U.S. infants and a major risk factor for childhood asthma. Growing evidence supports clinical heterogeneity within bronchiolitis. We aimed to identify endotypes of infant bronchiolitis by integrating clinical, virus, and serum proteome data, and examine their relationships with asthma development.This is a multicenter prospective cohort study of infants hospitalized for physician-diagnosis of bronchiolitis. We identified bronchiolitis endotypes by applying unsupervised machine learning (clustering) approaches to integrated clinical, virus (respiratory syncytial virus [RSV], rhinovirus [RV]), and serum proteome data measured at hospitalization. We then examined their longitudinal association with the risk for developing asthma by age 6 years.In 140 infants hospitalized with bronchiolitis, we identified three endotypes: (1) clinicalatopic virusRV proteomeNFκB-dysregulated , (2) clinicalnon-atopic virusRSV/RV proteomeTNF-dysregulated , and (3) clinicalclassic virusRSV proteomeNFκB/TNF-regulated endotypes. Endotype 1 infants were characterized by high proportion of IgE sensitization and RV infection. These endotype 1 infants also had dysregulated NFκB pathways (FDR < 0.001) and significantly higher risks for developing asthma (53% vs. 22%; adjOR 4.04; 95% CI, 1.49-11.0; p = 0.006), compared with endotype 3 (clinically resembling "classic" bronchiolitis). Likewise, endotype 2 infants were characterized by low proportion of IgE sensitization and high proportion of RSV or RV infection. These endotype 2 infants had dysregulated tumor necrosis factor (TNF)-mediated signaling pathway (FDR <0.001) and significantly higher risks for developing asthma (44% vs. 22%; adjOR 2.71; 95% CI, 1.03-7.11, p = 0.04).In this multicenter cohort, integrated clustering of clinical, virus, and proteome data identified biologically distinct endotypes of bronchiolitis that have differential risks of asthma development.
Categorization of Opioid Use Among Pregnant People and Association With Overdose or Death
Authors: Andi Camden, Teresa To, Joel G. Ray, Tara Gomes, Li Bai, Astrid Guttmann
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Early identification of people who use opioids in pregnancy may improve health outcomes for pregnant people and infants. However, characterization of diverse circumstances surrounding type of opioid use and indications for opioid use are lacking. <h3>Objective</h3> To develop clinically distinct groups of people who use opioids in pregnancy and to evaluate their association with drug overdose or death up to 1 year post partum. <h3>Design, Setting, and Participants</h3> This is a population-based, repeated cross-sectional study conducted in Ontario, Canada, with participants who used opioids in pregnancy who had a live birth or stillbirth between January 1, 2014, and December 31, 2019, identified in health administrative databases. Data were analyzed from August 2020 to January 2021. <h3>Exposures</h3> Prenatal opioid use. <h3>Main Outcomes and Measures</h3> Latent class analysis (LCA), based on prenatal opioid use and 19 socioeconomic and medical characteristics, first identified clinically distinct groups of opioid users. Then, within the optimally derived LCA-derived group, adjusted rate ratios (aRRs) were generated for the outcome of drug overdose or all-cause death within 1 year post partum, adjusting for birthing parent age and year of delivery. <h3>Results</h3> The analysis included 31 241 people with prenatal opioid use (mean [SD] age, 30.0 [5.6] years; 86.1% [26 908 individuals] Canadian-born; 30.6% [9574 individuals] lived in low-income neighborhoods). LCA generated a 5-group model that optimally distinguished opioid users in pregnancy as follows: short-term analgesia with low comorbidity (group 1), analgesia in young people (group 2), medication for opioid use disorder or unregulated opioid use (group 3), pain management with comorbidity (group 4), and mixed opioid use plus high social and medical needs (group 5). Using the 5-group model, compared with people in group 1, the aRR of overdose or death was highest among those in group 5 (aRR, 14.0; 95% CI, 10.1-19.5), followed by group 3 (aRR, 4.6; 95% CI, 3.3-6.5), group 2 (aRR, 3.3; 95% CI, 2.2-4.7), and group 4 (aRR, 3.2; 95% CI, 2.3-4.4). <h3>Conclusions and Relevance</h3> In this cross-sectional study, distinct groups of people with opioid use in pregnancy were associated with increased rates of postpartum drug overdose or death. Group characteristics can be used to identify people with high risk and inform harm reduction, home visiting programs, and other interventions.